Intensity modulated radiotherapy might be effective for locally advanced esophageal carcinosarcoma: A single center's experience and review of literature.
Esophageal carcinosarcoma is a rare type of esophageal cancer; however, few studies have investigated the effects of radiotherapy in locally advanced patients. This study aimed to report experience of the safety and efficacy of intensity-modulated radiotherapy for locally advanced esophageal carcinosarcoma and review the literature. By searching the institutional database between January 2010 and December 2020, along with the literature review, 25 patients were eligible for the study. The clinical and radiologic information of all patients with esophageal carcinosarcoma who underwent radiotherapy were collected. Survival outcomes were calculated using Kaplan-Meier plots. In our series, 5 patients were in the curative/neoadjuvant radiotherapy group and 10 patients were in the adjuvant group. Most tumors were protruding (n = 10, 66.7%). All patients underwent intensity-modulated radiotherapy. In the curative/neoadjuvant radiotherapy group, 2 patients underwent concurrent chemoradiotherapy before surgery, and the other three received radiotherapy alone as the initial treatment. The median follow-up time was 43.1 months. All patients showed a partial response at the efficacy evaluation. The median time of overall survival and progression-free survival were 40.2 months (95% confidence interval [CI], 13.1-67.3 months) and 19.0 months (95% CI, 13.9 months-24.1 months) for the entire cohort, but were not reached for curative/neoadjuvant radiotherapy group. Overall survival (hazard ratio [HR] 0.81, 95% CI, 0.15-4.43; P = .805) and progression-free survival (HR 1.68, 95% CI, 0.35-8.19; P = .514) did not differ significantly between the 2 groups. When considering the literature review data in the final analysis, overall survival (HR 0.84, 95% CI, 0.25-2.81; P = .779) and progression-free survival (HR, 0.68; 95% CI, 0.26-1.76; P = .425) were also not different between the 2 groups. Treatment based on intensity-modulated radiotherapy with neoadjuvant or curative intent may be an option for patients with unresectable esophageal carcinosarcoma. Further research with a larger sample size is needed to validate the reliability.


Does patient self-reported data have a role in the longitudinal study of Parkinson's disease? An analysis of the PROPATHtrade mark database.
Patient-reported data can be a valuable, adjunctive tool in helping physicians assess the quality-of-life and functional changes in patients with Parkinson's disease (PD). We analyzed and evaluated the largest PD patient-reported database (PROPATHtrade mark) relative to prescribing habits and changes in reported outcomes by therapy. Our analysis included 1436 patients, followed for 1 yr, who completed a series of questionnaires assessing medication therapy, daily activity scores adapted from the Unified Parkinson's Disease Rating Scale (UPDRS), global disease visual analogue scale, and health resources consumption. Our results indicated that physicians are prescribing Eldepryl(R) with increased frequency in patients with early and mild PD. Patients receiving Eldepryl alone or in combination with Sinemet(R) reported better outcomes than those receiving Sinemet monotherapy. There was a great deal of variability in the reported utilization of healthcare resources by patients in the PROPATH program and, thus, no statistical differences were noted for patients treated with different regimens. We conclude that the adjunctive use of longitudinal patient self-reported data programs such as PROPATH can help assess and improve overall patient outcomes. Future controlled studies should be conducted to further evaluate the roles of alternative therapies and patient-reported data in improving quality-of-life and outcomes for PD patients.


The thalamus and brainstem act as key hubs in alterations of human brain network connectivity induced by mild propofol sedation.
Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.


On the redox mechanism operating along C2H2 self-assembly at the surface of TiO2.
The interaction of acetylene with the TiO2 surface at room temperature entails a complex set of self-assembly reactions with the formation of products having relatively high molecular weight. In a previous paper by some of us (Jain, S. M.; et al. J. Mater. Chem. A 2014, 2, 12247-12254), the C2H2-TiO2 reaction has been monitored, essentially by Fourier transform infrared spectroscopy, at the surface of P25 (a mixture of anatase and rutile, typical benchmark material in the field of photocatalysis) in order to elucidate the nature of the products of this surface reaction. In the present paper, the same process was followed, for the first time, using electron paramagnetic resonance (EPR) and monitoring by the thermogravimetric analysis the weight loss of the material upon heating in order to further investigate the complex mechanism of the surface reaction. This was done using pure anatase and comparing the EPR results with those concerning both rutile and P25. The self-assembly mechanism occurring at the interface is accompanied by the formation of EPR visible Ti(3+) centers due to electrons injection in the TiO2 substrate. This finding clarifies that at least one of the reaction channels of this complex process (namely, the formation of polycyclic aromatic hydrocarbons) is based on the heterolytic dissociative chemisorption of acetylene, followed by a redox interaction between the adsorbate and the solid, which allows the creation of the building blocks necessary to assemble polyaromatic molecules.


Optimization of scan timing for aortic computed tomographic angiography using the test bolus injection technique.
With fast computed tomography (CT), it is possible for the scanning to outpace the contrast medium bolus during aortic CT angiography (CTA). To evaluate the effectiveness of a new method for reducing the risk of outpacing in which the scan start timing (ST) and speed can be estimated from the peak enhancement time measured at the femoral artery using a single test-bolus injection (femoral artery test injection method [FTI method]). In 30 cases of aortic CTA, we measured the time to peak enhancement at the femoral artery (TPF) and the ascending aorta (TPA) with test-bolus injection performed twice in each examination. From the resultant linear relationship between TPF and transit time (TT = TPF - TPA), we developed a method for determining the ST and TT from TPF. One hundred patients were assigned to two groups: FTI and bolus tracking (BT), each with 50 patients. CT values were measured in main vessels (ascending aorta, descending aorta, femoral artery). The CT values of the vessels and the rate of cases with more than 300 HU (good cases) were compared between the two groups. The enhancement in the FTI method was significantly higher than that of the BT method (average CT values: FTI, 388.3 ± 52.4; BT, 281.2 ± 59.1; P < 0.001). The rates of good cases for FTI and BT were 86.0% and 46.0%, respectively. The FTI method was very effective in reducing the risk of outpacing of the contrast medium transit in aortic CTA without the need for an additional contrast medium dose.


High intensity focused ultrasound in the treatment of breast fibroadenomata: results of the HIFU-F trial.
Breast fibroadenomata (FAD) are the most common breast lumps in women. High intensity focused ultrasound (HIFU) is a non-invasive ablative technique that can be used to treat FAD but is associated with prolonged treatment times. In the HIFU-F trial, we evaluated the change in volume over time with circumferential HIFU treatment of FAD and compared this to no treatment. Patients ≥18 years, diagnosed with symptomatic, palpable FAD, visible on ultrasound (US) were recruited. Twenty patients were treated using US-guided HIFU under local anaesthesia. Another 20 participants underwent an US 6 months after diagnosis. Outcome measures included: reduction in treatment time compared to whole lesion ablation; feasibility to achieve a 50% reduction in volume after 6 months; decrease in volume compared to a control group and reduction in symptoms. Circumferential ablation reduced the mean treatment time by 37.5% (SD 20.1%) compared to whole lesion ablation. US demonstrated a significant mean reduction in FAD volume of 43.5% (SD 38.8%; p = 0.016, paired t-test) in the HIFU group compared to 4.6% (SD 46.0%; p = 0.530) in the control group after 6 months. This mean reduction in FAD volume between the two groups was significant in favour of the HIFU group (p = 0.002, grouped t-test). Pre-treatment pain completely resolved in 6 out of 8 patients 6 months post-treatment. Circumferential HIFU ablation of FAD is feasible, with a significant reduction in pain and volume compared to control participants. It provides a simple, non-invasive, outpatient-based alternative to surgical excision for FAD.


Topical treatment of recurrent herpes simplex with cytosine arabinoside.
A double-blind controlled clinical trial of the topical use of cytosine arabinoside in recurrent herpes simplex of the face and genital region showed no significant difference in the efficiency of a placebo as compared with cytosine arabinoside. The high rate of placebo response (70%) found in this trial makes the assessment of any drug treatment for herpes simplex particularly difficult.


CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway.
As a rapid-progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs. The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing (scRNA-seq), immunostaining, real-time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co-immunoprecipitation, and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism. In this study, the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in the α-SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective "shield" to prevent the degradation of Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98. These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.


The role of inflammatory and parenchymal cells in acute pancreatitis.
The infiltration of inflammatory cells into the pancreas is an early and central event in acute pancreatitis that promotes local injury and systemic complications of the disease. Recent research has yielded the important finding that resident cells of the pancreas (particularly acinar and pancreatic stellate cells) play a dynamic role in leukocyte attraction via secretion of chemokines and cytokines and expression of adhesion molecules. Significant progress has been made in recent years in our understanding of the role of leukocyte movement (adhesion to the blood vessel wall, transmigration through the blood vessel wall and infiltration into the parenchyma) in the pathophysiology of acute pancreatitis. This review discusses recent studies and describes the current state of knowledge in the field. It is clear that detailed elucidation of the numerous processes in the inflammatory cascade is an essential step towards the development of improved therapeutic strategies in acute pancreatitis. Studies to date suggest that combination therapy targeting different steps of the inflammatory cascade may be the treatment of choice for this disease.


Terrein reduces age-related inflammation induced by oxidative stress through Nrf2/ERK1/2/HO-1 signalling in aged HDF cells.
This study investigated whether multiple bioactivity of terrein such as anti-inflammatory and anti-oxidant inhibits age-related inflammation by promoting an antioxidant response in aged human diploid fibroblast (HDF) cells. HDF cells were cultured serially for in vitro replicative senescence. To create the ageing cell phenotype, intermediate stage (PD31) HDF cells were brought to stress-induced premature senescence (SIPS) using hydrogen peroxide (H2 O2). Terrein increased cell viability even with H2O2 stress and reduced inflammatory molecules such as intracellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1β) and tumour necrosis factor-alpha (TNF-α). Terrein reduced also phospho-extracellular kinase receptor1/2 (p-EKR1/2) signalling in aged HDF cells. SIPS cells were attenuated for age-related biological markers including reactive oxygen species (ROS), senescence associated beta-galactosidase (SA β-gal.) and the aforementioned inflammatory molecules. Terrein induced the induction of anti-oxidant molecules, copper/zinc-superoxide defence (Cu/ZnSOD), manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) in SIPS cells. Terrein also alleviated reactive oxygen species formation through the Nrf2/HO-1/p-ERK1/2 pathway in aged cells. The results indicate that terrein has an alleviative function of age-related inflammation characterized as an anti-oxidant. Terrein might be a useful nutraceutical compound for anti-ageing.


Racemic versus l-epinephrine aerosol in the treatment of postextubation laryngeal edema: results from a prospective, randomized, double-blind study.
To determine whether any advantage exists using racemic epinephrine instead of the more potent and less expensive levo(1)-epinephrine in the treatment of postextubation laryngeal edema. Prospective, double-blind, randomized study. Pediatric intensive care unit in a university teaching hospital. Twenty-eight patients with stridor during the immediate postextubation period. After extubation, patients demonstrating clinically important stridor were randomized in a double-blind fashion to receive an aerosol containing either 2.25% racemic or 1% l-epinephrine. Heart rate, respiratory rate, blood pressure, and stridor score were determined at 20, 40, and 60 mins and 4 and 8 hrs after the initial aerosol administration. Patients in both groups demonstrated significant (p < .01) reductions in stridor score after aerosol administration. No significant differences were observed between treatment groups in improvement in stridor score or the number of subsequent aerosols required. Respiratory rate decreased significantly 40 and 60 mins after l-epinephrine but not after racemic epinephrine. No significant change in heart rate or blood pressure occurred after aerosol administration in either group. These data suggest that aerosolized l-epinephrine is as effective as aerosolized racemic epinephrine in the treatment of postextubation laryngeal edema without additional adverse side effects. When dosed appropriately, l-epinephrine is a less expensive and more widely available alternative to racemic epinephrine for the treatment of postextubation laryngeal edema.


PlenadrEMA: effect of dual-release versus conventional hydrocortisone on fatigue, measured by ecological momentary assessments: a study protocol for an open-label switch pilot study.
Patients with adrenal insufficiency have impaired health-related quality of life (QoL). The dual-release hydrocortisone preparation, Plenadren, has been developed to mimic the physiological cortisol release more closely than conventional hydrocortisone treatment. Plenadren has been shown to improve QoL, in particular fatigue, in patients with primary adrenal insufficiency. However, the effect has not been investigated in patients with secondary adrenal insufficiency; furthermore, no study has taken the diurnal variation of fatigue into account. To assess diurnal variations, it is necessary to use repeated daily measurements, such as ecological momentary assessments (EMAs). This study aims to evaluate EMAs of fatigue as outcome in future large-scale randomised clinical trials. The PlenadrEMA trial is an investigator-initiated open-label switch pilot trial of the effect of Plenadren versus conventional hydrocortisone on fatigue in patients with secondary adrenal insufficiency. The trial will include 30 participants. After 5 weeks on their usual hydrocortisone treatment, patients will be shifted to Plenadren for 16 weeks. Fatigue will be assessed using momentary versions of the Multidimensional Fatigue Inventory (MFI-20). Items will be administered to participants via a smartphone application four times daily during 20 days. Assessments will be performed before treatment shift and repeated after 12.5 weeks on Plenadren. The study will identify the best suited outcome for future randomised clinical trials, and in addition, estimate the variability and difference in fatigue between the two treatments to perform power calculations. The trial will be conducted in accordance with the Declaration of Helsinki and has been approved by the Regional Scientific Ethical Committee in Copenhagen (ID: H-1-2014-073). All patients will receive written and verbal information about the trial and will give informed consent before enrolment. Findings will be published in peer-reviewed journals and presented at international conferences. EudraCT201400203932.


New technique for quantitative bacteriological sampling of wounds by velvet pads: clinical sampling trial.
A new surface sampling method, the velvet pad rinse technique, was compared with the velvet pad imprint method, in a randomized bacteriological sampling trial, using surgical wounds to evaluate quantitative results. The efficiency of bacterial recovery was increased 20-fold by the new technique, and the improvement was ascribed in particular to the introduction of a procedure of rinsing the velvet pad after sampling.


Effect of different splitting techniques on the characteristics of divided tablets of five commonly split drug products in Jordan.
To determine the accuracy, variability, and weight uniformity of tablet subdivision techniques utilized to divide the tablets of five drug products that are commonly prescribed for use as half tablets in Jordan. Ten random tablets of five commonly subdivided drug products were weighed and subdivided using three subdivision techniques: hand breaking, kitchen knife, and tablet cutter. The five commonly subdivided drug products (warfarin 5 mg, levothyroxine 50 μg, levothyroxine 100 μg, candesartan 16 mg, and carvedilol 25 mg) were weighed. The weights were analyzed for acceptance, accuracy, and variability. Weight variation acceptance criteria were adopted in this work as a tool to indicate the properness of the subdivision techniques used to produce acceptable half tablets. Other relevant physical characteristics of the five products such as tablet shape, dimensions, face curvature, score depth, and crushing strength were measured. All tablets were round in shape, had weights that ranged between 100.63 mg (standard deviation=0.99) and 379.04 mg (standard deviation=3.00), and had crushing strengths that ranged between 23.29 N (standard deviation=3.58)and 103.35 N (standard deviation=14.98). Both candesartan and carvedilol were bi-convex in shape with an extent of face curvature equal to about 33%. In addition, percentage score depth of the tablets had a range between 0% and 24%. The accuracy and variability of subdivision varied according to the subdivision technique used and tablet characteristics. Accuracy range was between 81% and 109.8%. Moreover, the relative standard deviation was between 1.5% and 17.4%. Warfarin 5 mg subdivided tablets failed the weight variation test regardless of the subdivision technique used. Subdivision by hand produced half tablets that were acceptable for levothyroxine 50 μg and levothyroxine 100 μg. Subdivision by knife produced half tablets that were acceptable only for candesartan tablets. However, the tablet cutter produced half tablets that passed the weight variation test for four out of the five drug products tested in this study. The tablet cutter performed better than the other subdivision techniques used. It produced half tablets that passed the weight uniformity test for four drug products out of the five.


Factors associated with home deliveries in Thampalakamam, Trincomalee.
In Sri Lanka, more than 95% of women deliver in hospital. There is regional variation in the rate of home deliveries, and in some areas a significant number of mothers deliver at home. The objective of the present study was to identify the factors associated with home deliveries in Thampalakamam, Trincomalee. Ours was a community based, exploratory type of case control study. Cases were home deliveries during the period from Jan 1, 2000 to Dec 31, 2002 in Thampalakamam Divisonal Director of Health Services (DDHS) area. Controls were institutional deliveries among women residing in Thampalakamam DDHS area during the same period. A total of 139 cases and 278 controls were identified for this study. Data was collected at the household level using an interviewer-administered questionnaire. The following factors were found to have strong association with home deliveries: being a Muslim (OR = 33.0, 95% CI 16.8-64.8), low (< grade 5) maternal education (OR = 3.5, 95% CI 1.8-6.6), parity more than 3 (OR = 3.2, 95% CI 1.5-6.6) not being visited by a public health midwife (OR = 2.4, 95% CI 0.8-6.9), not being seen by a medical officer during the antenatal period (OR = 7.0, 95% CI 0.6-83.3). Lack of transport (35.5%) was mentioned as main reason for home deliveries by the women. Of the home deliveries 95% were assisted by a traditional birth attendant. Poor education of women and deficiencies in the delivery of antenatal care were found to be important risk factors for home deliveries.


Microfat grafting: the nurse's role.
Fat tissue is a complex and delicate structure that is easily damaged by mechanical and chemical insults. Structural microfat grafting involves the atraumatic harvest, cleansing, preparation, separation, and transplantation of small numbers of fat cells. The microfat grafting technique has been shown to successfully correct contour problems without resorption of the fat cells. Early work with fat transplantation, when the fat was injected subcutaneously or transplanted in bulk, was disappointing with significant loss of volume from central fat necrosis. Recent refinements in fat transplantation advocate the use of 1 to 2 mm threads of fat. This technique has been shown to improve contour problems or augment normal facial anatomy without resorption of the fat cells.


Aspirin and the Risk of Colorectal Cancer According to Genetic Susceptibility among Older Individuals.
Although aspirin has been considered a promising agent for prevention of colorectal cancer, recent data suggest a lack of benefit among older individuals. Whether some individuals with higher risk of colorectal cancer may benefit from aspirin remains unknown. We used a 95-variant colorectal cancer polygenic risk score (PRS) to explore the association between genetic susceptibility to colorectal cancer and aspirin use in a prospective study of 12,609 individuals of European descent ages ≥70 years, enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) double-blinded, placebo-controlled randomized trial (randomized controlled trial; RCT). Cox proportional hazards models were used to assess the association of aspirin use on colorectal cancer, as well as the interaction between the PRS and aspirin treatment on colorectal cancer. Over a median of 4.7 years follow-up, 143 participants were diagnosed with incident colorectal cancer. Aspirin assignment was not associated with incidence of colorectal cancer overall [HR = 0.94; 95% confidence interval (CI), 0.68-1.30] or within strata of PRS (P for interaction = 0.97). However, the PRS was associated with an increased risk of colorectal cancer (HR = 1.28 per SD; 95% CI, 1.09-1.51). Individuals in the top quintile of the PRS distribution had an 85% higher risk compared with individuals in the bottom quintile (HR = 1.85; 95% CI, 1.08-3.15). In a prospective RCT of older individuals, a PRS is associated with incident colorectal cancer risk, but aspirin use was not associated with a reduction of incident colorectal cancer, regardless of baseline genetic risk. There is strong evidence to support prophylactic aspirin use for the prevention of colorectal cancer. However recent recommendations suggest the risk of bleeding in older individuals outweighs the benefit. We sought to determine whether some older individuals might still benefit from aspirin based on their genetic susceptibility.


Association between p53 codon 72 polymorphisms and clinical outcome of nasopharyngeal carcinoma.
We conducted a cohort study to investigate whether polymorphisms in p53 at codon 72 are associated with tumor response and survival time of advanced nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. The study population included 127 subjects with NPC who were enrolled at Binzhou Medical University between September 2008 and December 2009. Cox proportional hazard regression was used to assess the association between polymorphisms in the p53 gene and progression-free survival (PFS) and overall survival (OS) of NPC patients. During the follow-up period, 42 patients died and 72 patients showed progression at the end of the study. Of the 127 patients, median PFS was 22.5 ± 1.2 months (1-36 months), and the median OS time was 28.2 ± 1.1 months (2-36 months). The p53 codon 72 Pro/Pro genotype was associated with a longer median PFS time of 30.3 months compared with 18.2 months for patients with Arg/Arg variants. Moreover, the p53 codon 72 Pro/ Pro genotype was associated with a longer median OS time of 31.6 months compared with 25.8 months for those with Arg/Arg variants; the P value was marginally significant. We showed that variants in p53 codon 72 may be an independent predictor for PFS and OS of NPC patients.


Patency of the aditus ad antrum in tubotympanic chronic suppurative otitis media.
To evaluate the patency of the aditus ad antrum in cases of tubotympanic chronic suppurative otitis media (CSOM) and to measure its dimensions. Also, to examine its mucosa histologically for the presence of granulation tissue or occult cholesteatoma. Prospective case series. Main Alexandria University Hospital (tertiary referral center). Fifty adult patients with tubotympanic CSOM without evidence of cholesteatoma, after adequate medical control of otorrhea, presented with mild or moderate conductive hearing loss. In all patients, tympanoplasty with cortical mastoidectomy was performed. The patency and dimensions of the aditus ad antrum were assessed using a 30° endoscope. Biopsies were obtained from unhealthy mucosa to detect the presence of granulation tissue or occult cholesteatoma. Ten cases (20%) had a blocked aditus ad antrum by unhealthy and edematous mucosa. Biopsies revealed granulation tissue in all cases. No occult cholesteatoma was detected. The results were further analyzed in relation to multiple variables to detect any clinical clues of a blocked aditus. Of the studied cases, 20% had a blocked aditus. The prevalence of an obstructed aditus was higher among older patients with a long history (>1 year) of ear discharge. Marginal and subtotal central perforations and the presence of myringosclerosis increase the probability of an obstructed aditus ad antrum.


MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway.
Our microRNA expression signature of renal cell carcinoma revealed that miR-218 expression was significantly decreased in cancer tissues, suggesting that miR-218 is a candidate tumor suppressor. We investigated the functional significance of miR-218 in cancer cells and identified what are to our knowledge novel miR-218 mediated cancer pathways in renal cell carcinoma. Gain of function studies using mature miR-218 were performed to investigate cell proliferation, migration and invasion in the A498 and 786-O renal cell carcinoma cell lines. To identify miR-218 mediated molecular pathways and responsible genes in renal cell carcinoma, we used gene expression and in silico database analyses. Loss of function assays were performed to investigate the functional significance of miR-218 target genes. Restoration of mature miR-218 significantly inhibited RCC cell proliferation, migration and invasion. Gene expression studies and luciferase reporter assays showed that CAV2 involved in the focal adhesion pathway was directly regulated by miR-218. A silencing study of CAV2 revealed significant inhibition of cell proliferation, migration and invasion. CAV2 mRNA and protein expression was significantly up-regulated in renal cell carcinoma clinical specimens. Loss of tumor suppressive miR-218 enhances cancer cell migration and invasion through dysregulation of the focal adhesion pathway, especially CAV2 as an oncogenic function in renal cell carcinoma. Tumor suppressive microRNA mediated cancer pathways and responsible genes provide new insights into the potential mechanisms of renal cell carcinoma oncogenesis and metastasis.


Smart Release Nano-formulation of Cytochrome C and Hyaluronic Acid Induces Apoptosis in Cancer Cells.
Herein we tested a nanosized cancer-cell targeted delivery system based on cytochrome c (Cyt c) and hyaluronic acid. Cyt c was chosen since it is a per se non-toxic protein but causes apoptosis when delivered to the cytoplasm of target cells. Hyaluronic acid was employed to create the nanosized delivery system with passive targeting capability in order to exploit the enhanced permeation and retention (EPR) effect and active targeting capability of hyaluronic acid. In addition, our goal was to incorporate a smart release strategy to only promote protein release upon reaching its target. Nanoparticles were formed by a simple yet precise nanoprecipitation process based on desolvation. They were physically characterized to select precipitation conditions leading to adequate size, shape, protein bioactivity, and protein loading to produce a feasible targeted cancer treatment. We synthesized nanoparticles of around 500 nm diameter with a 60% protein loading and more than 80% of protein bioactivity. In vitro, cumulative release of 92% of Cyt c was observed after 8 h under conditions mimicking the reductive intracellular environment, while under non-denaturing conditions only 20% was released. The nanoparticles displayed a selective cytotoxic effect on cancer cells. After 6 h of incubation with the nanoparticles, hyaluronic acid receptor over expressing A549 human lung adenocarcinoma cells showed a viability of ca. 20% at 0.16 mg/ml of Cyt c concentration. Only a negligible effect was observed on viability of COS-7 African green monkey kidney fibroblast, a normal cell line notoverexpressing the hyaluronic acid receptor. Confocal microscopy confirmed that the drug delivery system indeed delivered Cyt c to the cytoplasm of the target cells. We conclude that we were able to create a smart stimuli-responsive targeted drug delivery system with significant potential in cancer therapy.


Paternal investment and low birth weight - The mediating role of parity.
According to life-history theory, paternal investment affects the well-being of offspring. We hypothesized that environmental stress caused by a lack of paternal investment may diminish maternal resource allocation during pregnancy, especially for women who already have dependent children. Our study was conducted on a representative group of more than 80,500 singleton, live-born, full-term infants born in Krakow, Poland in the period 1995-2009. Birth data were obtained from the birth registry. We found that missing data about fathers (a proxy measure of low paternal investment) was associated with higher probability of multiparous mothers giving birth to low-birth-weight infants (1.48; 95% CI 1.05-2.08), but this was not the case with primiparous mothers (1.19; 95% CI 0.89-1.59). The statistically significant synergistic effect between parity and paternal investment was found (Synergy Factor = 2.12; 95% CI 1.47-3.05, p<0.001). These findings suggest that in situations of low paternal investment, multiparous mothers face trade-offs between investing in existing versus unborn children, therefore investment in the latter is lower. Such a strategy may benefit maternal fitness due to investment in older children, who have higher reproductive value.


Wet work exposure and hand eczema among healthcare workers: a cross-sectional study.
Hand eczema is more common in healthcare workers than in the general population. Hands are subject to changing occupational exposures as a result of mandatory hygiene regulations for healthcare workers. To describe exposure to hygiene procedures and investigate the associations between occupational hand washing, use of nonsterile gloves and hand disinfectant, and self-reported hand eczema. This was a cross-sectional study; an electronic questionnaire was distributed to 28 762 hospital employees in southern Sweden. Nurses, assistant nurses or physicians constituted the group of healthcare workers analysed. Adjustments were made for sex, age, wet work at home, lifestyle factors and atopic dermatitis. In total, 12 288 (43%) responded, including 9051 healthcare workers. In this group the 1-year prevalence of self-reported hand eczema was 21%. On a daily basis, 30% reported hand washing with soap > 20 times at work, 45% used hand disinfectants > 50 times and 54% wore nonsterile gloves for > 2 h. After adjustment for confounding factors, a dose-dependent association with self-reported hand eczema was found for the daily number of hand washes with soap at work and time working with disposable gloves but not for alcoholic disinfectant use. Hand washing outside work was not associated with self-reported hand eczema in the adjusted multivariate analysis. In this study, we found a higher 1-year prevalence of self-reported hand eczema among Swedish healthcare workers than reported in the general population. Hand washing with soap and use of disposable gloves were associated with the occurrence of self-reported hand eczema in a dose-dependent way. Use of hand disinfectant was not associated with self-reported hand eczema.


Positive Valence Bias in L2 Vocabulary Acquisition: Evidence From Chinese Emotion Idioms.
Positive valence bias refers to speakers responding faster to positive than negative information in L2 emotion words. Few researchers paid attention to the initial learning phase of L2 Chinese emotion idioms in which whether positive valence bias was acquired, based on the three-stage model of L2 vocabulary acquisition. Besides, whether the semantic information would modulate positive valence bias at the initial learning phase remained unclear. This study reports two experiments on speakers learning Chinese as a second language (CSL) to investigate positive valence bias in the initial learning phase of new Chinese emotion idioms and the modulation of semantic information on positive valence bias. Chinese as a second language speakers, who had acquired new Chinese emotion idioms and passed the test for learned Chinese idioms with a high accuracy rate before formal experiments, participated in Experiments 1 and 2. In Experiment 1, target materials were new Chinese idioms with positive and negative information. Positive valence bias at the initial learning phase of Chinese idioms was investigated with valence judgments. Experiment 2 used a semantic relatedness decision task further to explore the semantic effect on positive valence bias. The result in the first experiment showed that positive valence bias appeared in Chinese emotion idioms even at the initial learning phase of the acquisition. Meanwhile, semantic information of Chinese emotion idioms appeared to affect positive valence bias in the infant learning phase in Experiment 2. The findings revealed that semantic information would affect the performance of positive valence bias, suggesting that the semantic processing would automatically access the valence at the infant learning phase L2 Chinese emotion idioms. The research results provided evidence that positive valence bias would form in the infant learning phase of Chinese emotion idiom acquisition, based on the L2 vocabulary acquisition model.


Toward a unified representation of findings in clinical radiology.
The representations of findings in clinical radiology are heterogeneous. Motivations for developing a unified representation include the semantic integration of medical reports based on DICOM-SR(Digital Image Communication in Medicine Structured Reporting), bibliographic databases in the context of evidence-based medicine, and teaching resources. In this work, we propose a unified representation integrating the representations of findings in the UMLS, the GAMUTS in Radiology and the DICOM-SR. We analyse the UMLS and the DCMR (DICOM Content Mapping Resource) of DICOM SR to figure out their own representation of findings. Then we set up a syntax between the UMLS concepts using DICOM-SR relations in order to rewrite the GAMUTS sentences. The translation of the whole GAMUTS using the UMLS concepts and the DICOM SR syntax could be a method to create or supplement the DCMR TIDs (Template ID : Identifier of a Template) and CIDs (Context ID : Identifier of a Context Group) in the field of description of findings in medical imaging. This method could also enable to give an ontologic dimension to the DICOM SR representation system of information. The meaning of the CIDs would then be enhanced far beyond the simple use of the SNOMED vocabulary.


Germ cell restriction and regular transmission of an accessory chromosome that mimics a sex body in the zebra finch, Taeniopygia guttata.
Mitotic and meiotic analysis with light and electron microscopy was performed in male and female zebra finches (Taeniopygia guttata). Somatic cells from bone marrow have a 2n = 80 and show the usual sex chromosome mechanism of birds ZZ (male)/ZW (female). In the germ lines of both sexes, a single accessory chromosome was regularly present in all the cells examined from all the individual birds. In synaptonemal complex (SC) spreads of pachytene oocytes and spermatocytes, this accessory chromosome forms a single axis, but it behaves differentially in male and female meiosis. While this accessory chromosome is euchromatic in oocytes, it is strongly heterochromatic in spermatocytes. In pachytene spermatocytes, the accessory chromosome adopts a morphology strikingly similar to that of the XY body ('sex vesicle') of mammalian spermatocytes. This accessory chromosome is eliminated during male meiosis and forms a cytoplasmic dense body in young spermatids that shows strong fluorescence with DAPI. The presence of this germ line-restricted chromosome does not affect the behaviour of the ZW pair in oocytes, as the sex chromosomes pair regularly and show a localized recombination nodule. It is suggested that this accessory chromosome has transcriptional activity during oogenesis, and thus it is regularly transmitted through preferential segregation during female meiosis.


Fabrication of silica nanocapsules containing Ag/Au alloy nanoparticles by galvanic replacement reaction.
A straightforward method has been developed to generate silica nanocapsules containing Ag/Au alloy nanoparticles (Ag/Au@silica) by in-situ galvanic replacement reaction between the silica-coated silver (Ag@silica) nanoparticles with aqueous chloroauric acid (HAuCl4). Ag/Au@silica exhibits an optical absorbance derived from the surface Plasmon resonance of the encapsulated Ag/Au alloy nanoparticle. The behaviour of chemical diffusion across the silica shells of Ag/Au@silica is also investigated. It is worthy to noting that this facile synthetic strategy could be amenable to the other systems that involve the use of different combination of materials for the core (Pd/Ag, Pt/Ag alloy nanoparticles) and for the shell (titania).


Evaluation of a worksite injury and illness prevention program: do the effects of the REACH OUT training program reach the employees?
In this article the authors report the findings of a 2-year study evaluating the effectiveness of REACH OUT, a train-the-trainer program developed to assist small businesses comply with California legislation, Senate Bill 198 (1989), requiring employees to implement a worksite Injury and Illness Prevention Program. Data from a case study sample of 8 companies, drawn from 151 Southern California small businesses participating in the larger study, are reported. Diagnostic walk-throughs were performed, and employee surveys collected at the case study companies approximately 2 months before the treatment group received the intervention and again 1 year later. Results indicate that greater corporate compliance led to employees' perceptions of increased health and safety meetings and training sessions, which led to greater employee health and safety knowledge and improved employee health outcomes.


Manual asymmetry in a complex coincidence-anticipation task: handedness and gender effects.
This study investigated the effects of handedness and gender on manual asymmetry in the performance of a complex coincidence-anticipation task. Left-handed (N=63) and right-handed (N=93) undergraduate students (78 males, 78 females) were required to press six buttons sequentially in conjunction with visual stimulation provided by a coincidence-anticipation apparatus. Participants were further separated into subgroups based on the degree of hand preference. Timing accuracy (AE, CE, VE) and timing response (IT, MT, AT) were analysed. Results showed that, concerning accuracy, (i) strong left-handers were more accurate than the other groups; (ii) performance with the preferred hand was superior to that of the non-preferred hand; and (iii) males outperformed females. Concerning timing response, (i) the preferred hand was faster than the non-preferred hand for movement time and (ii) males were faster in initiating the movement than females. These findings indicate that coincidence-anticipation competence appears to be influenced by hand preference, performing hand, and gender. In addition, findings are discussed in the framework of the hemispheric functional lateralisation for the planning and organisation of movement execution.


Investigation of drug interactions with pinaverium bromide.
A series of studies was carried out at 6 centres to investigate possible drug interaction between the spasmolytic, pinaverium bromide, and cardiac glycosides, anticoagulants and hypoglycaemic agents given to patients as part of the long-term treatment of their condition. The results of clinical and laboratory investigations did not show any evidence of pinaverium bromide interfering with the action or activity of any of the drugs studied.


Alternating hemidystonia following traumatic brain injury as an unusual presentation of paroxysmal autonomic instability with dystonia syndrome.
A 20-year-old man presented to the neurotrauma intensive care unit following blunt head injury. MRI revealed subarachnoid haemorrhage and multiple intraparenchymal haemorrhages suggesting severe brain injury. During recovery, the patient displayed intermittent episodes of alternating hemibody spasms with decerebrate/decorticate dystonic posturing. Episodes presented with autonomic dysregulation including hyperthermia, diaphoresis, tachypnoea, tachycardia and hypertension. Concern for seizure activity prompted simultaneous video monitoring and EEG testing. Results were without epileptiform activity suggesting against seizure as cause for alternating hemibody spasms. Paroxysmal autonomic instability with dystonia (PAID) was considered despite the unusual presentation. Intravenous hydromorphone was used for treatment, which relieved symptoms of autonomic dysregulation and dystonic posturing. PAID syndrome was diagnosed based on presentation with intermittent episodes of dystonia, autonomic dysregulation, absence of epileptiform activity and rapid response to opioid treatment. This case illustrates the clinical variability of this uncommon syndrome because alternating hemidystonia as main manifestation has not been previously described.


Inhibition by 2-arachidonoylglycerol, a novel type of possible neuromodulator, of the depolarization-induced increase in intracellular free calcium in neuroblastoma x glioma hybrid NG108-15 cells.
2-Arachidonoylglycerol was found to inhibit the depolarization-induced increase in [Ca2+]i in NG108-15 cells differentiated with prostaglandin E1 and theophylline in a dose-dependent manner. Such an effect appears to be rather specific to polyunsaturated fatty acid-containing monoacylglycerols such as 2-arachidonoylglycerol. Neither 2-palmitoylglycerol nor free arachidonic acid exhibited appreciable inhibitory activity. These observations raise the possibility that 2-arachidonoylglycerol attenuates the increase in [Ca2+]i, thereby modulating several neural functions in this type of cell.


Unusually high fluorescence quantum yield of a homopolyfluorenylazomethine--towards a universal fluorophore.
The absolute fluorescence quantum yield (Φfl) of a polyfluorenyl azomethine homopolymer was measured as a function of solvent polarity. The solvent induced and temperature dependent fluorescence of the homopolymer were also investigated and they were compared to the corresponding monomer and copolymer. The Φfl of the homopolymer was consistent (45-70%), regardless of solvent polarity with Stokes shifts up to 7460 cm(-1) in ethanol. In contrast, the Φfl of its corresponding monomer decreased from 60% in ethanol to 1% in toluene, whereas a Φfl < 5% for its analogous copolymer was measured. Moderate fluorescence yields (Φfl ≈ 25%) were also possible in thin film when co-depositing the homopolymer with PMMA. Cryofluorescence was used to probe the excited state deactivation modes. Deactivation by internal conversion was found to compete with fluorescence. The fluorescence deactivation pathways of the homopolymer and its corresponding monomer could be suppressed at 77 K, resulting in fluorescence turn-on. Both fluorophores were found to detect nitroaromatics.


Subspace Weighting Co-Clustering of Gene Expression Data.
Microarray technology enables the collection of vast amounts of gene expression data from biological experiments. Clustering algorithms have been successfully applied to exploring the gene expression data. Since a set of genes may be only correlated to a subset of samples, it is useful to use co-clustering to recover co-clusters in the gene expression data. In this paper, we propose a novel algorithm, called Subspace Weighting Co-Clustering (SWCC), for high dimensional gene expression data. In SWCC, a gene subspace weight matrix is introduced to identify the contribution of gene objects in distinguishing different sample clusters. We design a new co-clustering objective function to recover the co-clusters in the gene expression data, in which the subspace weight matrix is introduced. An iterative algorithm is developed to solve the objective function, in which the subspace weight matrix is automatically computed during the iterative co-clustering process. Our empirical study shows encouraging results of the proposed algorithm in comparison with six state-of-the-art clustering algorithms on ten gene expression data sets. We also propose to use SWCC for gene clustering and selection. The experimental results show that the selected genes can improve the classification performance of Random Forests.


Islamic fasting: cardiovascular disease perspective.
Ramadan is a month of obligatory fasting observed by the majority of 2 billion Muslims living around the globe. The guidelines for 'risk-free' fasting exist for chronic diseases, including diabetes mellitus, but recommendations for cardiovascular disease (CVD) patients are deficient due to the paucity of literature. Databases were screened to find relevant studies for an evidence-based consensus regarding the risk stratification and management of CVD. Using practical guidelines of the European Society of Cardiology (ESC), we categorized patients into low-, moderate-, and high-risk categories and proposed a pre-Ramadan checklist for the assessment of cardiac patients before fasting. Regular moderate-intensity exercise is recommended for most cardiac patients, which has been demonstrated to provide an anti-inflammatory and antioxidant effect that improves immune function. In Ramadan, many physiological changes occur during fasting, which brings about a balanced metabolic homeostasis of the body. In addition, Ramadan fasting is a nonpharmacologic means of decreasing CV risk factors. As Islam exempts Muslims from fasting if they are unwell; therefore, patients with the acute coronary syndrome (ACS), advanced heart failure (HF), recent percutaneous coronary intervention (PCI), or cardiac surgery should avoid fasting.


Heart size-independent analysis of myocardial function in murine pressure overload hypertrophy.
Pressure overload cardiac hypertrophy may be a compensatory mechanism to normalize systolic wall stress and preserve left ventricular (LV) function. To test this concept, we developed a novel in vivo method to measure myocardial stress (sigma)-strain (epsilon) relations in normal and hypertrophied mice. LV volume was measured using two pairs of miniature omnidirectional piezoelectric crystals implanted orthogonally in the endocardium and one crystal placed on the anterior free wall to measure instantaneous wall thickness. Highly linear sigma-epsilon relations were obtained in control (n = 7) and hypertrophied mice produced by 7 days of transverse aortic constriction (TAC; n = 13). Administration of dobutamine in control mice significantly increased the load-independent measure of LV contractility, systolic myocardial stiffness. In TAC mice, systolic myocardial stiffness was significantly greater than in control mice (3,156 +/- 1,433 vs. 1,435 +/- 467 g/cm(2), P < 0.01), indicating enhanced myocardial contractility with pressure overload. However, despite the increased systolic performance, both active (time constant of LV pressure decay) and passive (diastolic myocardial stiffness constant) diastolic properties were markedly abnormal in TAC mice compared with control mice. These data suggest that the development of cardiac hypertrophy is associated with a heightened contractile state, perhaps as an early compensatory response to pressure overload.


Glyphosate affects larval gut microbiota and metamorphosis of honey bees with differences between rearing procedures.
The honey bee Apis mellifera is a sentinel species of the pollinator community which is exposed to a wide variety of pesticides. In the last half-century, the pesticide most applied worldwide has been the herbicide glyphosate (GLY) used for weed control and with microbiocide effects. After its application in crops, the GLY residues have been detected in flowers visited by honey bees as well as in the stored food of their hives. Therefore, the honey bee brood can ingest the herbicide during larval development. Recent studies proved that GLY has detrimental effects on adult honey bees and other insects associated with the disturbance of their gut microbiota. GLY induces changes in the growth, metabolism and survival of honey bees and stingless bees reared in vitro. However, the effect of GLY on larval microbiota is unknown so far and there are few studies with an in-hive exposure to GLY. For these reasons, this study aims to determine whether GLY induces dysbiosis in honey bee larvae and affects their metamorphosis during the exposure period (pre-defecation) and the post-exposure period. Furthermore, we assessed this herbicide in vitro and in the hive to compare its effects on different rearing procedures. Finally, we tested the pigment BLUE1 as an indirect exposure marker to detect and estimate the in-hive intake concentration of GLY. Our results indicate that the intake of field-relevant concentrations of GLY induced a slowdown in growth with dysbiosis in the larval gut microbiota followed by late effects on their metamorphosis such as teratogenesis and mortality of newly emerged bees. Nevertheless, brood from the same colonies expressed different signs of toxicity depending on the rearing procedure and in a dose-dependent manner.


Case report: laparoscopic cholecystectomy in situs viscerum inversus.
Situs viscerum inversus is a rare condition, in which the organs are transposed from their normal location in the opposite side of the body. The inversion of L-R asymmetry may be complete (SVI totalis) or partial (SVI partialis), whereby transposition is confined to either the abdominal or thoracic viscera. The authors report a case of videolaparocholecystectomy for cholelithiasis successfully performed on a 41-year-old Caucasian woman with situs viscerum inversus totalis. The patient was discharged on the 2nd postoperative day. The symptomatology disappeared right after the intervention, and still now, after a follow-up of six months, is absent. The procedure was safely performed on the patient with no particular difficulties, except for the reverse position of the angle between the operating and exposing trocars, which led to a difficult approach to the Calot triangle when using the right hand of the surgeon.


Wisconsin Card Sorting Test performance impairment in schizophrenia: An Indian study report.
The present study attempted to find out the relationship between positive and negative clinical symptoms and Wisconsin Card Sorting Test (WCST) performance in a group of schizophrenia patients. Fifty schizophrenia patients were assessed using the Positive and Negative Syndrome Scale (PANSS) by a trained psychiatrist (TKA) and two groups, each of 25 positive symptom and 25 negative symptom schizophrenia patients were formed. On these fifty patients with schizophrenia and 15 normal control groups, WCST measures were applied by a clinical psychologist (SS) who remained blind to the PANSS score. Schizophrenia diagnosis significantly affects WCST performances. One-way analysis of variance (ANOVA) revealed schizophrenia patients showed a significant impairment on all WCST indices compared with normal subjects except versus total number of correct responses. Post hoc comparison (Tukey HSD Test) between means revealed that negative schizophrenia patients showed significantly worse performance on most WCST performance parameters: percent errors, perseverative responses, percent perseverative responses, perseverative errors, percent perseverative errors, and conceptual level responses. Both positive and negative symptom schizophrenia patients have some distinct WCST measures deficits.


Parametric analysis of breast MRI.
Parametric analysis of breast MRI provides unique mapping of pathophysiological characteristics that cannot be obtained by standard conventional MRI. We describe in this review methods based on intrinsic contrast and tissue elasticity as well as methods that use external paramagnetic contrast agents and follow the time evolution of contrast. Processing of the raw data, frequently with new mathematical models and algorithms, yielded calculated parametric images that may help improve the noninvasive detection and diagnosis of breast cancer.


Antagonist activity of [Thr18,gamma-methylleucine19]endothelin-1 in human endothelin receptors.
Receptor binding and antagonist properties of endothelin-1 analogues, [Thr18,gamma-methylleucine19]endothelin-1, [Thr18,Leu19]endothelin-1 and [Thr18,cyclohexylalanine19]endothelin-1, were investigated using cloned human endothelin ET(A) and ET(B) receptors expressed in Chinese hamster ovary cells. Among them, [Thr18,gamma-methylleucine19]endothelin-1 had a high affinity for endothelin ET(A) and ET(B) receptors with respective Kd values of 300 and 110 pM and had no agonist activity on the stimulation of arachidonic acid release in endothelin ET(A) and ET(B) receptor-expressing cells. [Thr18,gamma-methylleucine19]Endothelin-1 had potent antagonist activity in endothelin-1-induced arachidonic acid release in endothelin ET(A) and ET(B) receptor-expressing cells with respective pA2 values of 8.2 and 8.5. In an inositol phosphates accumulation assay, [Thr18,gamma-methylleucine19]endothelin-1 also exhibited potent antagonist activity for endothelin ET(A) and ET(B) receptors with respective pA2 values of 8.0 and 8.4. In conclusion, [Thr18,gamma-methylleucine19]endothelin-1 acts as a potent and nonselective antagonist with no agonist activity for cloned human endothelin ET(A) and ET(B) receptors.


Ethical aspects of arranging local medical collaboration and care.
Yearly pediatric cardiac surgery missions to Ghana are of tremendous benefit to local children, but may create thorny ethical dilemmas for local clinicians who refer and screen children for the mission and who provide care to the children after the mission concludes for the year. This article presents the experiences and concerns of a pediatrician who is a local member of the Hearts and Minds of Ghana project.


An Ethyl-Thioglycolate-Functionalized Fe3O4@ZnS Magnetic Fluorescent Nanoprobe for the Detection of Ag+ and Its Applications in Real Water Solutions.
Ethyl-thioglycolate-modified Fe3O4@ZnS nanoparticles (Fe3O4@ZnS-SH) were successfully prepared using a simple chemical precipitation method. The introduction of ethyl thioglycolate better regulated the surface distribution of ZnS, which can act as a recognition group and can cause a considerable quenching of the fluorescence intensity of the magnetic fluorescent nanoprobe, Fe3O4@ZnS-SH. Benefiting from stable fluorescence emission, the magnetic fluorescent nanoprobe showed a highly selective fluorescent response to Ag+ in the range of 0-400 μM, with a low detection limit of 0.20 μM. The magnetic fluorescent nanoprobe was used to determine the content of Ag+ in real samples. A simple and environmentally friendly approach was proposed to simultaneously achieve the enrichment, detection, and separation of Ag+ and the magnetic fluorescent nanoprobe from an aqueous solution. These results may lead to a wider range of application prospects of Fe3O4 nanomaterials as base materials for fluorescence detection in the environment.


Phosphorylation of Rho-associated kinase (Rho-kinase/ROCK/ROK) substrates by protein kinases A and C.
Rho-associated kinase (Rho-kinase/ROCK/ROK) is a serine/threonine kinase and plays an important role in various cellular functions. The cAMP-dependent protein kinase (protein kinase A/PKA) and protein kinase C (PKC) are also serine/threonine kinases, and directly and/or indirectly take part in the signal transduction pathways of Rho-kinase. They have similar phosphorylation site motifs, RXXS/T and RXS/T. The purpose of this study was to identify whether sites phosphorylated by Rho-kinase could be targets for PKA and PKC and to find peptide substrates that are specific to Rho-kinase, i.e., with no phosphorylation by PKA and PKC. A total of 18 substrates for Rho-kinase were tested for phosphorylation by PKA and PKC. Twelve of these sites were easily phosphorylated. These results mean that Rho-kinase substrates can be good substrates for PKA and/or PKC. On the other hand, six Rho-kinase substrates showing no or very low phosphorylation efficiency (<20%) for PKA and PKC were identified. Kinetic parameters (K(m) and k(cat)) showed that two of these peptides could be useful as substrates specific to Rho-kinase phosphorylation.


Evaluation of retromolar canals on cone beam computerized tomography scans and digital panoramic radiographs.
The purpose of this study was to carry out morphologic and topographic analyses of retromolar canals on cone beam computerized tomography (CBCT) scans, comparing findings to others obtained from the corresponding digital panoramic radiographs. Sixty-one CBCT scans were analysed digitally, as well as their corresponding digital panoramic radiographs. The prevalence and distribution of these canals, foramen diameters, and intraosseous communications were also evaluated. On CBCT scans, we found that 24.6% of individuals had at least one retromolar canal. The mean foramen diameter was slightly higher than 1 mm and we could not determine the intraosseous anatomical connections in most cases. The morphology and topography of the retromolar canals were not affected by gender and antimere. In addition, only 22.2% of all tomographically identified canals could be confirmed on digital panoramic radiographs (26.7% of such patients). Regarding all sample, 6.6% of individuals showed retromolar canals on digital panoramic radiographs. We may consider that these structures are clinically relevant findings and, due to the low accuracy of the panoramic radiographs, high-quality tomographic exams should always be asked for presurgical treatment planning.


Facilitating Active Species Generation by Amorphous NiFe-Bi Layer Formation on NiFe-LDH Nanoarray for Efficient Electrocatalytic Oxygen Evolution at Alkaline pH.
Searching for a simple and fast strategy to effectively enhance the oxygen evolution reaction (OER) performance of non-noble-metal electrocatalysts in alkaline media remains a significant challenge. Herein, the OER activity of NiFe-LDH nanoarray on carbon cloth (NiFe-LDH/CC) in alkaline media is shown to be greatly boosted by an amorphous NiFe-Borate (NiFe-Bi ) layer formation on NiFe-layered double hydroxide (NiFe-LDH) surface. Such a NiFe-LDH@NiFe-Bi /CC catalyst electrode only needs an overpotential of 294 mV to drive 50 mA cm-2 in 1.0 m KOH; 116 mV less than that needed by NiFe-LDH/CC. Notably, this electrode also demonstrates strong long-term electrochemical durability. The superior activity is ascribed to the pre-formed amorphous NiFe-Bi layer effectively promoting active species generation on the NiFe-LDH surface. This work opens up exciting new avenues for developing high-performance water-oxidation catalyst materials for application.


Short-term changes in renal function in children and adolescents undergoing extracorporeal shock wave lithotripsy.
Aim To identify short-term effects of extracorporeal shock wave lithotripsy (ESWL) on renal function in children and adolescents with single kidney stones. Methods In a 4-year period 30 children (15 boys and 15 girls) from 10 to 18 years of age were treated for unilateral renal stones with ESWL. Inclusion criteria were: up to 18 years of age, kidney stone (from 4 to 20 mm in diameter) visible on X-ray, first ESWL treatment, unilateral lithotripsy treatment without previous kidney surgery, patients without infravesical obstruction, patients without proven urinary infection, repeated use of one (the same) analgesic, patients without anticoagulant and antihypertensive therapy, patients without use of nephrotoxic drugs prior to and during the treatment, normal blood pressure, non-pregnancy patients with normal renal function. Serum enzymes (alkaline phosphatase, lactate dehydrogenase), cystatin C, serum and urine electrolytes (sodium, potassium, chloride), and urine neutrophil gelatinase-associated lipocalin (uNGAL) were tested before, on the first and fifth day after the treatment. Results An increase of alkaline phosphatase and lactate dehydrogenase was statistically significant on day 1 (p<0.05) and values returned to normal on day 5. Serum cystatin C level was also significantly increased during the first four days after ESWL treatment (p<0.05) and returned to baseline on post-treatment day 5. There was a statistically significant difference in the level of uNGAL in urine before and 24 hours after ESWL treatment (p<0.05). Conclusion The ESWL is a safe and curative procedure for the treatment of kidney stones in children and adolescents with no evidence of serious adverse effects on renal function.


Hyperglycemia accelerates arterial thrombus formation and attenuates the antithrombotic response to endotoxin in mice.
Recent human studies reveal that hyperglycemia induces procoagulant and antifibrinolytic effects in blood that may contribute to a greater risk of arterial thrombosis, but the direct relationship between high blood glucose levels and thrombosis has not yet been investigated. We performed a number of experiments to clarify whether hyperglycemia was causally related to arterial thrombosis and whether the combined stimulus of hyperglycemia and inflammation would enhance the thrombotic effect. In a model of ferric-chloride-induced carotid artery thrombosis, hyperglycemia did not influence the time to occlusion in mice pretreated with streptozotocin, but the rate of thrombus formation was accelerated. This effect was associated with increased thrombin generation and could not be explained by changes in vessel-wall tissue factor activity. The prothrombotic effect of hyperglycemia was assessed in a separate experiment, showing that collagen/thrombin-induced platelet procoagulant activity was increased in hyperglycemic mice. The effect of inflammation was studied by injecting a low dose of endotoxin that caused a systemic inflammatory state after 24 h (increased plasma levels of tumor necrosis factor alpha, interleukin-6 and monocyte chemotactic protein 1 in diabetic and nondiabetic mice) associated with a mild delay in thrombus formation. This reduced rate of thrombus formation was attenuated by hyperglycemia. Together, these data establish a discrete but clear contribution of hyperglycemia in experimental arterial thrombosis.


Theory of transformation thermal convection for creeping flow in porous media: Cloaking, concentrating, and camouflage.
Heat can transfer via thermal conduction, thermal radiation, and thermal convection. All the existing theories of transformation thermotics and optics can treat thermal conduction and thermal radiation, respectively. Unfortunately, thermal convection has seldom been touched in transformation theories due to the lack of a suitable theory, thus limiting applications associated with heat transfer through fluids (liquid or gas). Here, we develop a theory of transformation thermal convection by considering the convection-diffusion equation, the equation of continuity, and the Darcy law. By introducing porous media, we get a set of equations keeping their forms under coordinate transformation. As model applications, the theory helps to show the effects of cloaking, concentrating, and camouflage. Our finite-element simulations confirm the theoretical findings. This work offers a transformation theory for thermal convection, thus revealing novel behaviors associated with potential applications; it not only provides different hints on how to control heat transfer by combining thermal conduction, thermal convection, and thermal radiation, but also benefits mass diffusion and other related fields that contain a set of equations and need to transform velocities at the same time.


Relationship between cognitive impairment and serum amyloid β-protein, adiponectin, and C-reactive protein levels in type II diabetes patients.
This study sought to explore the plausible mechanism of the cognitive impairment of patients with type 2 diabetes by analyzing the levels of serum amyloid β-protein (Aβl-42), adiponectin, and C-reactive protein (CRP). Eighty-four patients diagnosed with type 2 diabetes and 60 healthy people were selected as the participants for this study. Clinical data were collected using self-made questionnaires. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale was used to access cognitive functions. The serum Aβl-42 and adiponectin levels were individually determined by an enzyme-linked immunoassay (ELISA). CRP was detected using a Siemens BNP II specific-protein analyzer. Patients in the case group had significantly lower immediate memory, visual span, speech function, attention, and delayed memory scores on the RBANS scale than patients in the control group. The Aβl-42 levels of patients in case group were significantly higher than those of patients in the control group. The age of patients was significantly negatively correlated to RBANS scale subtest scores and standard scores in the case group. The number of years of schooling was significantly positively correlated to immediate memory, visual span, attention, delayed memory scores, and standard scores, but negatively correlated with speech function. After adjusting for age and the number of years of schooling, the Aβl-42 levels of patients in the case group were significantly negatively correlated with immediate memory, attention, delayed memory scores, and standard scores (P<0.05). The adiponectin levels of patients in the case group were positively correlated with RBANS scale subtest scores and standard scores (P<0.05). Type 2 diabetes patients suffered from cognitive impairment. It appears that the mechanism may be associated with increased serum Aβl-42 levels, decreased adiponectin levels and inflammation reaction. The detection of serum Aβl-42 and adiponectin could be used as indicators of the degree of cognitive impairment in patients with type 2 diabetes.


Intracholecystic papillary-tubular neoplasm of gallbladder: A 5-year retrospective pathological study.
Intracholecystic papillary-tubular neoplasm (ICPN) is a relatively new entity which includes neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm. This study is done to evaluate the pathological features of ICPN and to find out the factors associated with invasion. This is a 5-year retrospective study in a referral pathology center. A total of 19 cases of ICPN are found. The cases are analyzed for age and sex distribution, clinical suspicion, stages, histological architecture, differentiation, and grade of dysplasia. Descriptive statistics and test of significance by Chi-square and t-test are used in the study. ICPN comprises 23.5% of all gallbladder neoplasms. Two-thirds of the cases were suspected radiologically. Age range is 26-65 years with mean age of 50 years. They are 2.8 times more common in female. Approximately one-third of the cases show invasion. The most common histological pattern is papillary, followed by papillary-tubular and finally by tubular pattern. Pyloric and biliary are the most common differentiation pattern followed by oncocytic and intestinal pattern. About three-fourths of the cases are associated with high-grade dysplasia mostly diffuse high-grade dysplasia. We have found the younger age of presentation, less proportion of invasive tumors, fewer tumors with biliary phenotypes, and fewer tumors with high-grade dysplasia as compared to previous studies. Factors significantly associated with invasion are grade and extent of dysplasia particularly diffuse high-grade dysplasia.


Prenatal diagnosis of anomalous origin of the right pulmonary artery from the ascending aorta.
We report a case of anomalous origin of the right pulmonary artery from the ascending aorta that was diagnosed by fetal ultrasound at 21 weeks of gestation. The clue to the diagnosis was present in the three-vessel view, this being one of the views that we use for fetal cardiac screening. The anomaly was corrected surgically at 11 days of age. We discuss the importance of prenatal diagnosis in the management of this rare anomaly.


Impact of the COVID-19 Pandemic on Colorectal Cancer Care in the Netherlands: A Population-based Study.
The COVID-19 pandemic disrupted health care services worldwide. In the Netherlands, the first confirmed COVID-19 infection was on February 27, 2020. We aimed to investigate the impact of the pandemic on colorectal cancer care in the Netherlands. Colorectal cancer patients who were diagnosed in 25 hospitals in weeks 2 to 26 of the year 2020 were selected from the Netherlands Cancer Registry (NCR) and divided in 4 periods. The average number of patients treated per type of initial treatment was analyzed by the Mantel-Haenszel test adjusted for age. Median time between diagnosis and treatment and between (neo)adjuvant therapy and surgery were analyzed by the Mann Whitney test. Percentages of (acute) resection, stoma and (neo)adjuvant therapy were compared using the Chi-squared test. In total, 1,653 patients were included. The patient population changed during the COVID-19 pandemic regarding higher stage and more clinical presentation with ileus at time of diagnosis. Slight changes were found regarding type of initial treatment. Median time between diagnosis and treatment decreased on average by 4.5 days during the pandemic. The proportion of colon cancer patients receiving a stoma significantly increased with 6.5% during the pandemic. No differences were found in resection rate and treatment with (neo)adjuvant therapy. Despite the disruptive impact of the COVID-19 pandemic on global health care, the impact on colorectal cancer care in the Netherlands was limited.


Scale Dependence of Female Ungulate Reproductive Success in Relation to Nutritional Condition, Resource Selection and Multi-Predator Avoidance.
Female ungulate reproductive success is dependent on the survival of their young, and affected by maternal resource selection, predator avoidance, and nutritional condition. However, potential hierarchical effects of these factors on reproductive success are largely unknown, especially in multi-predator landscapes. We expanded on previous research of neonatal white-tailed deer (Odocoileus virginianus) daily survival within home ranges to assess if resource use, integrated risk of 4 mammalian predators, maternal nutrition, winter severity, hiding cover, or interactions among these variables best explained landscape scale variation in daily or seasonal survival during the post-partum period. We hypothesized that reproductive success would be limited greater by predation risk at coarser spatiotemporal scales, but habitat use at finer scales. An additive model of daily non-ideal resource use and maternal nutrition explained the most (69%) variation in survival; though 65% of this variation was related to maternal nutrition. Strong support of maternal nutrition across spatiotemporal scales did not fully support our hypothesis, but suggested reproductive success was related to dam behaviors directed at increasing nutritional condition. These behaviors were especially important following severe winters, when dams produced smaller fawns with less probability of survival. To increase nutritional condition and decrease wolf (Canis lupus) predation risk, dams appeared to place fawns in isolated deciduous forest patches near roads. However, this resource selection represented non-ideal resources for fawns, which had greater predation risk that led to additive mortalities beyond those related to resources alone. Although the reproductive strategy of dams resulted in greater predation of fawns from alternative predators, it likely improved the life-long reproductive success of dams, as many were late-aged (>10 years old) and could have produced multiple litters of fawns. Our study emphasizes understanding the scale-dependent hierarchy of factors limiting reproductive success is essential to providing reliable knowledge for ungulate management.


Shape optimization in unsteady blood flow: a numerical study of non-Newtonian effects.
This paper presents a numerical study of non-Newtonian effects on the solution of shape optimization problems involving unsteady pulsatile blood flow. We consider an idealized two dimensional arterial graft geometry. Our computations are based on the Navier-Stokes equations generalized to non-Newtonian fluid, with the modified Cross model employed to account for the shear-thinning behavior of blood. Using a gradient-based optimization algorithm, we compare the optimal shapes obtained using both the Newtonian and generalized Newtonian constitutive equations. Depending on the shear rate prevalent in the domain, substantial differences in the flow as well as in the computed optimal shape are observed when the Newtonian constitutive equation is replaced by the modified Cross model. By varying a geometric parameter in our test case, we investigate the influence of the shear rate on the solution.


PAGAT gel dosimetry for everyone: gel production, measurement and evaluation.
Polymer gel (PG) dosimetry is a valuable tool to measure complex dose distributions in 3D with a high spatial resolution. However, due to complex protocols that need to be followed for in-house produced PGs and the high costs of commercially available gels, PG gels are only rarely applied in quality assurance procedures worldwide. In this work, we provide an introduction to perform highly standardized dosimetric PG experiments using PAGAT (PolyAcrylamide Gelatine gel fabricated at ATmospheric conditions) dosimetry gel. PAGAT gel can be produced at atmospheric conditions, at low costs and is evaluated using magnetic resonance imaging (MRI). The conduction of PG experiments is described in great detail including the gel production, treatment planning, irradiation, MRI evaluation and post-processing procedure. Furthermore, a plugin in an open source image processing tool for post-processing is provided free of charge that allows a standardized and reproducible analysis of PG experiments.


Cardiovascular involvement in 8 dogs with blastomyces dermatitidis infection.
Blastomycosis is a common systemic fungal infection in dogs. Dogs with cardiovascular involvement may have abnormalities in electrical conduction and valvular function, and may have a worse prognosis. Eight client-owned animals. Dogs with cardiovascular lesions caused by blastomycosis were identified from retrospective evaluation of medical records. Five dogs had de novo infections and 3 had recurrences of previously treated infections. Harsh labored breathing, lethargy, and anorexia were the most common historic complaints. Three dogs had syncope. Physical examination and clinicopathologic data were typical of blastomycosis and included dyspnea, increased lung sounds, and lethargy. In addition, 3 dogs had heart murmurs and 1 had a third-degree atrioventricular block. Four dogs had myocarditis and 2 had pericarditis or epicarditis. Two dogs had cardiac signs attributed to extracardiac compression by fungal granulomas and clinical signs were relieved by treatment. Half of the remaining 6 dogs were euthanized; 2 of these were not treated. Of the remaining 3 dogs, 1 dog died acutely while sleeping; the second died intraoperatively during an attempt to place an epicardial pacemaker; and the third had Blastomyces-induced endocarditis and died of heart failure. Blastomycosis should be considered in the differential diagnosis of dogs from endemic areas with inflammatory myocarditis, heart block, heart base or intracardiac mass lesions, syncope, or endocarditis.


Early implementation of intended exercise improves quality of life in Parkinson's disease patients.
Recent data have shown that regular exercise may ameliorate motor symptoms in Parkinson's disease (PD). This study aims to investigate how intended exercise impacts motor and non-movement symptoms of PD. Eighty-eight patients were randomly assigned to an early exercise group (E-EG), late exercise group (L-EG), or a control group (CG) using a randomized delayed-start design. The E-EG carried out a rigorous, formal exercise program for 1 h, twice per week, for 18 months (May 2018-November 2019). The L-EG took part in the exercise program in the final 6-12 months of the study. We assessed outcomes using the Unified Parkinson's Disease Rating Scale (UPDRS), PDQ-39 Questionnaire, Line A test, Line B test, Nine-hole column test, 30 s squat and stand-up test (30 s SST), 10-m walk test (10mW), Balance Evaluation Systems Mini Test (MiniBESTest), FAB, and Time Up and Go Test (TUG). The patients with PD in the E-EG had lower performance in the UPDRS and Line B test compared to those in the L-EG at post-exercise (p < 0.05). Moreover, the patients with PD in the E-EG had much lower performance in the PDQ-39 and 9-Hole Peg test compared to those in the L-EG at post-exercise (p < 0.01). Implementation of an exercise regimen improved the movement abilities and quality of life in PD patients, especially in the E-EG. This data supports the idea that intended exercise should be implemented as part of the treatment strategy for PD patients as early as possible.


Evidence for a Notch1-mediated transition during olfactory ensheathing cell development.
Olfactory ensheathing cells (OECs) are a unique glial population found in both the peripheral and central nervous system: they ensheath bundles of unmyelinated olfactory axons from their peripheral origin in the olfactory epithelium to their central synaptic targets in the glomerular layer of the olfactory bulb. Like all other peripheral glia (Schwann cells, satellite glia, enteric glia), OECs are derived from the embryonic neural crest. However, in contrast to Schwann cells, whose development has been extensively characterised, relatively little is known about their normal development in vivo. In the Schwann cell lineage, the transition from multipotent Schwann cell precursor to immature Schwann cell is promoted by canonical Notch signalling. Here, in situ hybridisation and immunohistochemistry data from chicken, mouse and human embryos are presented that suggest a canonical Notch-mediated transition also occurs during OEC development.


Influence of light intensity on surface-free energy and dentin bond strength of single-step self-etch adhesives.
In this study, we investigated the influence of light intensity on the surface-free energy and dentin bond strength of single-step selfetch adhesives. The adhesives were applied to the dentin surfaces of bovine mandibular incisors and cured with light intensities of 0 (no irradiation), 200, 400, and 600 mW/cm(2). Surface-free energies were determined by measuring the contact angles of three test liquids placed on the cured adhesives. Dentin bond strengths of the specimens were also measured. Polymerization with a higher light intensity resulted in a lower surface-free energy of the cured adhesives. The greatest bond strength was achieved when a light intensity of 400 mW/cm(2) or greater was used. Our data suggest that the surface-free energy and dentin bond strength of single-step self-etch adhesives are affected by light intensity of the curing unit.


The effects of lesions to the postsubiculum or the anterior dorsal nucleus of the thalamus on spatial learning in rats.
To investigate the role of the head direction (HD) cell circuit in spatial navigation, rats with bilateral, neurotoxic lesions to the postsubiculum (PoS; Experiment 1) or the anterior dorsal nucleus of the thalamus (ADN; Experiment 2) were compared to sham controls on 2 tasks that could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from 2 locations in the experimental room. ADN lesioned rats were impaired relative to sham controls on the first block of 8 trials, but not on the total trials taken to reach criterion. This transient deficit was not observed in rats with lesions to the PoS. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table, and return to the home cage. Both PoS and ADN lesioned rats showed impairments on this task relative to sham rats, making more errors on the return component of the foraging trip. The spatial deficits produced by lesions to the PoS and the ADN, downstream structures in the HD cell circuit, are not as severe as those observed in earlier studies in rats with lesions to the dorsal tegmental nucleus.


Exposure to Toluene Di-isocyanate and Respiratory Effects in Flexible Polyurethane Foam Industries in Western India.
Flexible foam industry largely uses 2,4 and 2,6 Toluene di-isocyanate as main raw materials and chronic exposure to its result in occupational asthma. The exposure to di-isocyanates might be higher due to the usage of obsolete technology, hand-mixing methods and working in confined spaces with insufficient local exhaust ventilation systems in developing countries. Exposure studies in flexible foam industries have not been done in developing countries. The present cross-sectional study was conducted to evaluate toluene di-isocyanate (TDI) exposures and respiratory health of the workers working in the seven flexible polyurethane foam industries located in Western India during 2010-2013. A total of 128 personal air samples collected and evaluated for total TDI concentration using improved Occupational Safety and Head Administration method number 42. Then 194 workers were covered for complete clinical examination and spirometry for assessing respiratory health. In all, 17.83% of air samples exceeded the ACGIH TWA-TLV of 0.005 ppm for TDI. Though only 11 (5.6%) workers had respiratory complaints, the spirometry revealed that 19 (9.8%) and four (2.1%) had restrictive and obstructive type of pulmonary function impairment, respectively. The TWA concentration of TDI exceeded at raw material storage, mixing, foaming, block cutting and curing areas in four out of seven industries even in the presence of local exhaust systems. The respiratory health effect is less when compared to exposure to TDI, suitable preventive and control measures were suggested based on the study findings to the stakeholders to prevent the increase of respiratory health effects.


"Big Data" Fast Chemoinformatics Model to Predict Generalized Born Radius and Solvent Accessibility as a Function of Geometry.
The Generalized Born (GB) solvent model is offering the best accuracy/computing effort ratio yet requires drastic simplifications to estimate of the Effective Born Radii (EBR) in bypassing a too expensive volume integration step. EBRs are a measure of the degree of burial of an atom and not very sensitive to small changes of geometry: in molecular dynamics, the costly EBR update procedure is not mandatory at every step. This work however aims at implementing a GB model into the Sampler for Multiple Protein-Ligand Entities (S4MPLE) evolutionary algorithm with mandatory EBR updates at each step triggering arbitrarily large geometric changes. Therefore, a quantitative structure-property relationship has been developed in order to express the EBRs as a linear function of both the topological neighborhood and geometric occupancy of the space around atoms. A training set of 810 molecular systems, starting from fragment-like to drug-like compounds, proteins, host-guest systems, and ligand-protein complexes, has been compiled. For each species, S4MPLE generated several hundreds of random conformers. For each atom in each geometry of each species, its "standard" EBR was calculated by numeric integration and associated to topological and geometric descriptors of the atom neighborhood. This training set (EBR, atom descriptors) involving >5 M entries was subjected to a boot-strapping multilinear regression process with descriptor selection. In parallel, the strategy was repurposed to also learn atomic solvent-accessible areas (SA) based on the same descriptors. Resulting linear equations were challenged to predict EBR and SA values for a similarly compiled external set of >2000 new molecular systems. Solvation energies calculated with estimated EBR and SA match "standard" energies within the typical error of a force-field-based approach (a few kilocalories per mole). Given the extreme diversity of molecular systems covered by the model, this simple EBR/SA estimator covers a vast applicability domain.


Differentiation of Effect Across Systemic Literacy Programs in Rwanda, the Philippines, and Senegal.
In this article, we compare three localized applications (in Rwanda, Senegal, and the Philippines) of a literacy approach for resource-lean environments and examine the factors influencing its impact in each context, considering dosage, duration, and environment. In Rwanda, a bilingual early grade literacy initiative implemented in partnership with the ministry of education included literacy standards development, training for early grade teachers, materials development, leadership support, and community-based activities. In the Philippines, a primary grades trilingual curriculum was implemented in close collaboration with the Department of Education to strengthen its literacy component through standards development, teacher and school leader training, materials development, and awareness campaigns. Finally, in Senegal, a program was conducted supporting the YMCA's efforts to improve local educational outcomes by training youth volunteers to mentor students at risk and by engaging families and communities.


A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure.
The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that a recently identified gene of yet unknown function, termed SA, which is differentially expressed in the kidney of the spontaneously hypertensive rat, cosegregates with an increase in blood pressure in F2 rats derived from a cross of the spontaneously hypertensive rat with normotensive Wistar-Kyoto rats, accounting for 28 and 21% of the genetic variability in systolic and diastolic blood pressures, respectively. Further, the genotype at this locus appears to determine the level of expression of the gene in the kidney. The findings provide strong evidence for a primary genetic involvement of the kidney in hypertension.


Evaluation of intralesional injection of hyaluronic acid compared with verapamil in Peyronie's disease: preliminary results from a prospective, double-blinded, randomized study.
Several intralesional therapeutic protocols have been proposed for the treatment of Peyronie's disease. Among all, hyaluronic acid (HA) and verapamil have been differently tested. We aimed to evaluate the efficacy of intralesional verapamil (ILVI) compared with intralesional HA in patients with early onset of Peyronie's disease (PD). This is a multi-centre prospective double-arm, randomized, double-blinded study comparing ILVI vs. intralesional HA after 12-weeks. Sexually active men, older than 18 years and affected by the acute phase of PD were eligible for this study. Patients have been double-blinded randomly divided into two groups (1 : 1 ratio): Group A received intralesional treatment with Verapamil (10 mg in 5 mL of normal saline water) weekly for 12 weeks, while group B received intralesional treatment with HA (0.8% highly purified sodium salt HA 16 mg/2 mL) weekly for 12 weeks. The primary efficacy outcome was the change from the baseline to the endpoint (12 weeks after therapy) for the penile curvature (degree). The secondary outcome was the change in the plaque size and in the International Index of erectile Function (IIEF-5) score. The difference between post- and pre-treatment plaque size was -1.36 mm (SD ± 1.27) for Group A and -1.80 mm (SD ± 2.47) for Group B (p-value = NS). IIEF-5 increased of 1.46 points (SD ± 2.18) in Group A and 1.78 (SD ± 2.48) in Group B (p-value ± NS). No difference in penile curvature was observed in Group A, while in Group B the penile curvature decreased of 4.60° (SD ± 5.63) from the baseline (p < 0.001) and vs. Group A. According to PGI-I results, we found significant difference as concerning patient global impression of improvement (PGI-I) (4.0 vs. 2.0; p < 0.05). This prospective, double-arm, randomized, double-blinded study comparing ILVI vs. HA as intralesional therapy showed greater efficacy of HA in terms of penile curvature and PGI-I.


Membrane trafficking of angiotensin receptor type-1 and mechanochemical signal transduction in proximal tubule cells.
Cellular localization and trafficking of the major angiotensin receptor, AT1, was studied in mouse proximal tubule cell lines because angiotensin II concentrations in the luminal fluid of proximal tubules are greater than the K(d) of the receptor and would predict high turnover rates of the receptor. Mouse proximal tubule cells can exist in 2 polarized, differentiated states after confluence: a protoepithelium and a highly differentiated epithelium. The latter is distinguished by greater polarization of the microtubule cytoskeleton and collection of apical microtubule-dependent membrane proteins in condensed apical recycling endosomes (CARE) in proximity to the primary cilium. AT1, AT2, and the sodium hydrogen exchanger NHE3 are localized to CARE. With fluid movement, AT1 receptors externalize from CARE to the apical plasma membrane and allow luminal angiotensin II to initiate cell signaling. These data suggest that fluid movement controls receptor externalization and, hence, a model in which ciliary deflection results in transduction of a mechanical stimulus into the chemical signaling of the AT1 receptor.


Autologous blood donation and subsequent blood use in patients undergoing total knee arthroplasty.
Autologous blood donation is designed to avoid complications from allogeneic blood, leaving units of blood in the general blood supply. It is unclear how efficient these programmes are in accomplishing these goals. It is unclear if autologous donation provokes increased need for any transfusion following surgery and whether it can be avoided in low-risk surgeries. Of 430 patients undergoing unilateral primary knee replacement arthroplasty over 12 months in our hospital, 309 had autologous donations and 121 did not. Of the 121 patients who did not donate, 36% completed surgery without transfusion, whereas only 17% of those who had autologous donations did so (P < 0.05). Age less than 65 years, higher baseline and postoperative haemoglobin levels were associated with lower transfusion rates. Patients who had autologous donations were approximately four times more likely to be transfused. As the number of autologous units donated increased, transfusions following surgery increased. Autologous donation did reduce allogeneic blood transfusions. Therefore, autologous blood donation for unilateral total knee arthroplasty is associated with overall increased transfusion rates, but with reduced need for allogeneic blood, independent of other clinical factors associated with transfusion. Therefore, there is need for reconsideration of these programmes relative to specific surgeries.


Crystal structure of silkworm Bombyx mori JHBP in complex with 2-methyl-2,4-pentanediol: plasticity of JH-binding pocket and ligand-induced conformational change of the second cavity in JHBP.
Juvenile hormones (JHs) control a diversity of crucial life events in insects. In Lepidoptera which major agricultural pests belong to, JH signaling is critically controlled by a species-specific high-affinity, low molecular weight JH-binding protein (JHBP) in hemolymph, which transports JH from the site of its synthesis to target tissues. Hence, JHBP is expected to be an excellent target for the development of novel specific insect growth regulators (IGRs) and insecticides. A better understanding of the structural biology of JHBP should pave the way for the structure-based drug design of such compounds. Here, we report the crystal structure of the silkworm Bombyx mori JHBP in complex with two molecules of 2-methyl-2,4-pentanediol (MPD), one molecule (MPD1) bound in the JH-binding pocket while the other (MPD2) in a second cavity. Detailed comparison with the apo-JHBP and JHBP-JH II complex structures previously reported by us led to a number of intriguing findings. First, the JH-binding pocket changes its size in a ligand-dependent manner due to flexibility of the gate α1 helix. Second, MPD1 mimics interactions of the epoxide moiety of JH previously observed in the JHBP-JH complex, and MPD can compete with JH in binding to the JH-binding pocket. We also confirmed that methoprene, which has an MPD-like structure, inhibits the complex formation between JHBP and JH while the unepoxydated JH III (methyl farnesoate) does not. These findings may open the door to the development of novel IGRs targeted against JHBP. Third, binding of MPD to the second cavity of JHBP induces significant conformational changes accompanied with a cavity expansion. This finding, together with MPD2-JHBP interaction mechanism identified in the JHBP-MPD complex, should provide important guidance in the search for the natural ligand of the second cavity.